Bottom Line:
The incidences of PNI, lymph node metastasis, high serum CA19-9 level, cancers in the body/tail, and advanced pathological stage were associated with shorter OSs.In the PNI(+) group, lymph node metastasis and high levels of TAM infiltration were associated with worse prognoses.PNI(+) status and high levels of TAM infiltration further worsen the prognosis.

Objectives: Tumor-associated macrophages (TAMs) are thought to be involved in the perineural invasion (PNI) process and to be associated with poor prognoses. The associations between TAMs, PNI, and clinicopathological features in pancreatic ductal adenocarcinomas (PDAs) remain to be elucidated.

Methods: Fifty-nine PDA patients who had undergone pancreaticoduodenectomy were retrospectively examined. The PNI statuses and TAMs were reviewed following H&E staining and S-100, CD68, and CD163 immunohistochemical staining. The relationships between PNI, TAMs, and overall survival and various clinical and histopathologic factors were investigated.

Results: PNI was identified in 83% (49/59) of the cases, the TAM density of the PNI(+) group was greater than that of the PNI(-) group, and the infiltrating TAMs around the nerves that were invaded by cancer were much more numerous than those around the nerves without cancer cell invasion. The incidences of PNI, lymph node metastasis, high serum CA19-9 level, cancers in the body/tail, and advanced pathological stage were associated with shorter OSs. In the PNI(+) group, lymph node metastasis and high levels of TAM infiltration were associated with worse prognoses.

Conclusions: TAMs might enhance PNI, and the incidence of PNI was associated with poor prognosis. PNI(+) status and high levels of TAM infiltration further worsen the prognosis. Therapies targeting TAMs might represent auxiliary and preventive treatment for PNI in PDA patients.

Mentions:
Macrophages are one of the most common inflammatory cell types involved in the host stromal response to cancer cell invasion 16. To explore the macrophage response to PNI, we evaluated the TAM densities and patterns of macrophage infiltration around the nerves in pathological specimens excised from 59 patients with PDAs. As shown in Figure 1, the macrophages were studied with immunolabeling for the macrophage marker CD68, the M2-type macrophages marker CD163, and S-100 staining of the nerves. Table 1shows the relationship between the macrophages and PNI. The numbers of CD68+and CD163+ cells within the PDA lesions in the PNI+ group were higher than those of the PNI- group (105 ± 3.77 vs. 86 ± 9.57 for the CD68+ cells, P = 0.04; and 73 ± 4.83 vs. 46 ± 8.04 for the CD163+ cells, P = 0.017, respectively.). Although there was no significant relationship between the macrophage counts and PNI grades, infiltrating CD68+and CD163+ cells were much more commonly found around the nerves that had been invaded by cancer than around those that had not (7.92 ± 0.81 vs. 4.47 ± 0.55 CD68+ macrophages/nerve, P = 0.000, and 4.98 ± 0.62 vs. 3.03 ± 0.57 CD163+ macrophages/nerve, P = 0.001, respectively). Notably, the nerves in the PDAs lesion that had not been invaded by cancer cells were surrounded by greater numbers of CD68+and CD163+ cells than were the nerves in the benign areas of pancreatic tissues (4.47 ± 0.55 vs. 2.00 ± 0.71 CD68+ macrophages/nerve, P = 0.000, and 3.03 ± 0.57 vs. 0.23 ± 0.17 CD163+ macrophages/nerve, P = 0.018, respectively, Figure 2), which indicates that the TAMs enhanced cancer cell invasion along the nerves.

Mentions:
Macrophages are one of the most common inflammatory cell types involved in the host stromal response to cancer cell invasion 16. To explore the macrophage response to PNI, we evaluated the TAM densities and patterns of macrophage infiltration around the nerves in pathological specimens excised from 59 patients with PDAs. As shown in Figure 1, the macrophages were studied with immunolabeling for the macrophage marker CD68, the M2-type macrophages marker CD163, and S-100 staining of the nerves. Table 1shows the relationship between the macrophages and PNI. The numbers of CD68+and CD163+ cells within the PDA lesions in the PNI+ group were higher than those of the PNI- group (105 ± 3.77 vs. 86 ± 9.57 for the CD68+ cells, P = 0.04; and 73 ± 4.83 vs. 46 ± 8.04 for the CD163+ cells, P = 0.017, respectively.). Although there was no significant relationship between the macrophage counts and PNI grades, infiltrating CD68+and CD163+ cells were much more commonly found around the nerves that had been invaded by cancer than around those that had not (7.92 ± 0.81 vs. 4.47 ± 0.55 CD68+ macrophages/nerve, P = 0.000, and 4.98 ± 0.62 vs. 3.03 ± 0.57 CD163+ macrophages/nerve, P = 0.001, respectively). Notably, the nerves in the PDAs lesion that had not been invaded by cancer cells were surrounded by greater numbers of CD68+and CD163+ cells than were the nerves in the benign areas of pancreatic tissues (4.47 ± 0.55 vs. 2.00 ± 0.71 CD68+ macrophages/nerve, P = 0.000, and 3.03 ± 0.57 vs. 0.23 ± 0.17 CD163+ macrophages/nerve, P = 0.018, respectively, Figure 2), which indicates that the TAMs enhanced cancer cell invasion along the nerves.

Bottom Line:
The incidences of PNI, lymph node metastasis, high serum CA19-9 level, cancers in the body/tail, and advanced pathological stage were associated with shorter OSs.In the PNI(+) group, lymph node metastasis and high levels of TAM infiltration were associated with worse prognoses.PNI(+) status and high levels of TAM infiltration further worsen the prognosis.

Objectives: Tumor-associated macrophages (TAMs) are thought to be involved in the perineural invasion (PNI) process and to be associated with poor prognoses. The associations between TAMs, PNI, and clinicopathological features in pancreatic ductal adenocarcinomas (PDAs) remain to be elucidated.

Methods: Fifty-nine PDA patients who had undergone pancreaticoduodenectomy were retrospectively examined. The PNI statuses and TAMs were reviewed following H&E staining and S-100, CD68, and CD163 immunohistochemical staining. The relationships between PNI, TAMs, and overall survival and various clinical and histopathologic factors were investigated.

Results: PNI was identified in 83% (49/59) of the cases, the TAM density of the PNI(+) group was greater than that of the PNI(-) group, and the infiltrating TAMs around the nerves that were invaded by cancer were much more numerous than those around the nerves without cancer cell invasion. The incidences of PNI, lymph node metastasis, high serum CA19-9 level, cancers in the body/tail, and advanced pathological stage were associated with shorter OSs. In the PNI(+) group, lymph node metastasis and high levels of TAM infiltration were associated with worse prognoses.

Conclusions: TAMs might enhance PNI, and the incidence of PNI was associated with poor prognosis. PNI(+) status and high levels of TAM infiltration further worsen the prognosis. Therapies targeting TAMs might represent auxiliary and preventive treatment for PNI in PDA patients.